Clopidogrel (methyl(+)-(S)-α-(o-chlorophenyl)-6,7-dihydrothieno[3,2-a]pyridine-5(4H)-acetate), the compound of formula (II) is known as a useful medicament for the treatment and prevention of various platelet-associated vascular diseases such as stroke, cerebral arteriosclerosis, myocardial infarction, angina pectoris, arrhythmia, peripheral arteries disease, and Burger's disease (see European Patent No. 281,459 B1 and U.S. Pat. No. 4,847,265).

However, clopidogrel itself as free base form is an oil which is difficult to purify, and the ester group thereof liable to hydrolysis to produce the acid of formula (III) which has no biological activity. Also, under moist and heat conditions, it can be transformed to the levorotatory isomer of formula (IV) having much less pharmacological activity. Accordingly, there has been a need to convert clopidogrel to a crystalline form which is very stable and easily purifiable, and for the purpose, it is common to make an acid addition salt using a pharmaceutically acceptable inorganic or organic acid.

European Patent No. 281,459 B1 and U.S. Pat. No. 4,847,265 disclose a number of acid addition salts of clopidogrel prepared using various inorganic or organic acids. However, it is described that most of these salts are amorphous, hygroscopic and/or low melting, which are improper to use in pharmaceutical composition. Even the claimed crystalline salts such as hydrochloride, hydrobromide, hydrogen sulfate, and taurocholate, have some problems. The taurocholate is unsuitable for use as a pharmaceutically acid addition salt of clopidogrel because taurocholic acid itself has another pharmacological activity, i.e., bile secretion. Also it was confirmed by the inventors that the hydrochloride and hydrobromide salts are highly hygroscopic under a condition of 60° C. temperature and 75% relative humidity, resulting in gum type or liquefied form.
Furthermore, it is known that clopidogrel hydrogen sulfate employed in PLAVIX® (Sanofi-Synthelabo Inc.), a marketed tablet composition (see European Patent No. 281,459 B1 and U.S. Pat. No. 6,429,210), is also not sufficiently stable (see H. Agrawal et al, Talanta, 61: 581-589, 2003). For example, it was reported PLAVIX® is unstable under an accelerated test condition (40° C., 75% relative humidity, for 3 months), producing significant amounts of impurities (see Y. Gomez et al, J. Pharm. Biomed. Anal. 34: 341-348, 2004). In addition, clopidogrel hydrogen sulfate has two polymorphic forms which differ from each other in terms of physicochemical properties, and one of the two forms can be contaminated into the other during its manufacture varying from batch to batch. This makes it difficult to maintain a pharmaceutically required homogeneous polymorphic state.
Accordingly, there has been a need for the better salt of clopidogrel. The inventors have unexpectedly found that crystalline naphthalenesulfonate of clopidogrel is optically pure, less hygroscopic, and more stable toward moisture and heat than conventional acid addition salts. Thus, a pharmaceutical composition comprising same is effective for the prevention or treatment of platelet-associated vascular diseases.